A number of compounds used in the pharmaceutical industry, including active pharmaceutical ingredients (APIs), are labile in acid media. This causes numerous problems when it comes to developing a pharmaceutical formulation for oral administration due to the fact that when said acid labile compounds come into contact with the stomach content, which is a strongly acidic environment, degradation occurs. To avoid contact between acid labile compounds and gastric juice after oral administration of said compounds, solid pharmaceutical dosage forms have been developed that comprise a bead that contains the acid labile compound and an external layer that constitutes a gastro-resistant coating, also known as enteric coating. See, for example, chapters 45, 46, 47 of “Remington, the science and practice of pharmacy”, 21st Edition, 2005, Ed. Lippincott Williams & Wilkins, for a discussion on coatings, concretely, pages 932-933 regarding enteric coatings. However, said gastro-resistant coatings are frequently acid and therefore the acid labile compounds need to be protected. Examples of this situation are benzimidazole compounds, of which omeprazol [(±)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-3H-benzoimidazole] is its most representative example, and which are APIs widely known as effective gastric acid secretion inhibitors. Benzimidazol compounds of biological interest also include pantoprazole, rabeprazole, lansoprazole or (−)-(S)-5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-3H-benzoimidazole, also known as esomeprazol (EP 652872), which is the levorotatory enantiomer of omeprazol.
A solution to the acid lability problem has been to introduce a separating layer between the acid labile compounds and the gastro-resistant coating. For example, EP 1020460 B1 discloses a pellet of esomeprazole sodium having a separating layer with hydroxypropyl methylcellulose as unique ingredient and an enteric coating comprising hydroxypropyl methylcellulose phtalate.
EP 244380, EP 733025, EP 1086694 and EP1185254 disclose omeprazole formulations having a separating layer comprising hydroxypropyl methylcellulose.
A different solution is to create an alkaline environment around the acid labile compound by, for example, using alkaline salts of the compound and/or incorporating a compound of alkaline reaction in the pharmaceutical solid dosage form (see, for example, EP 0 244 380 and U.S. Pat. No. 4,786,505).
Other documents also describe separating layers when formulating acid labile APIs.
However, in addition to the stability problem in acid media, some compounds, e.g. esomeprazol sodium salt, are extremely soluble in water, which makes their formulation very difficult, especially when using the aqueous layering process. This process comprises dispersing/dissolving the API and the rest of the pharmaceutical ingredients in water and making a spray-dry process or a fluid bed pulverization process at 40° approximately. When preparing the dosage form, said compounds migrate to the separating layer, or even to the enteric coating, due to their solubility in the water used in the process. This is detrimental to the stability of the compounds as it places them in contact with the acidic environment of the enteric coating.
As a consequence, the problems of avoiding the protonic transfer from the enteric coat to the core that contains the acid labile compound, or of avoiding the migration of the acid labile compound from an internal layer to an external one turn to be an important concern.
Thus, in order to provide a suitable formulation of acid labile compounds, there is an existing need to avoid both, the migration of the acid labile compounds to outer coating layers, but also the proton transfer from said outer layers to the internal layer containing the acid labile active ingredient. In order to achieve this the separating layer should be readily soluble in water, as it has to be dissolved in the human body (once the enteric coat is dissolved, in the neutral or nearly neutral pH conditions of the intestine, the API has to be released fast), but at the same time it should effectively act as a barrier in order to stop proton transfer to the core and avoid API migration to the enteric coat. Either of these unwanted migrations will affect negatively to the API's stability.
The aqueous layering process frequently used to apply the separating layer, exposes it to water and relative high temperatures (usually up to 50° C.) and, thus, makes it vulnerable to migration of water, dissolution or dispersion of the layer during the process. Also care should be taken when the enteric coat is applied over the separating layer, in order to avoid water migration through the same or into de core.
Many separating layers have been tested (hydroxypropyl methylcellulose alone (HPMC), Polyvinyl Alcohol, etc. . . . ) in order to avoid the above mentioned problems. However, no completely satisfactory configuration has been proposed.